There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin. The primary lesion in this state involves defects in the uptake and storage of glucose in muscle and fat cells. Insulin stimulates glucose uptake in these cells by increasing the concentration of the facilitative transporter Glut4 at the cell surface. The molecular events involved in this process will be investigated, with special attention to the underlying basis for the specificity of actions of the hormone. We have learned that small G proteins coordinately integrate signals from the insulin receptor to control the trafficking of Glut4. Previous studies have revealed a central role for the G protein TC10 in this process.
In Aim 1, we will study the biochemical processes involved in the activation and inactivation of TC10, investigating the molecular details that explain the unique properties of this protein, and attempting to understand how it is regulated by insulin via the control of crucial upstream activators. We will also study how its activity is turned off by inactivating proteins.
In Aim 2, we will create mice with a targeted deletion of the gene encoding TC10 to explore the role of this G protein in a physiological setting. We will evaluate glucose and lipid metabolism in these mice, anticipating that deletion of this gene may significantly alter insulin action. Finally, in Aim 3, we will evaluate a specific pathway downstream of TC10 that controls the trafficking of the Glut4 protein to the plasma membrane in cells. This pathway involves another G protein, Rab31;we hypothesize that the activity of this protein is negatively regulated by insulin through TC10 activation. We will explore the role of a newly discovered Rab31 activator named Gapex-5 in this process, and how its effect on Rab31 is regulated by control of its cellular location. Together, these approaches will allow for the evaluation of the importance of this novel pathway in insulin action, setting the stage for future investigations into its potential role in the development of diabetes.
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